Comprehensive molecular profiling of multiple myeloma identifies refined copy number and expression subtypes
Open accessAbstract
Multiple myeloma is a treatable, but currently incurable, hematological malignancy of plasma cells characterized by diverse and complex tumor genetics for which precision medicine approaches to treatment are lacking. The Multiple Myeloma Research Foundation’s Relating Clinical Outcomes in Multiple Myeloma to Personal Assessment of Genetic Profile study ( NCT01454297 ) is a longitudinal, observational clinical study of newly diagnosed patients with multiple myeloma (n = 1,143) where tumor samples are characterized using whole-genome sequencing, whole-exome sequencing and RNA sequencing at diagnosis and progression, and clinical data are collected every 3 months. Analyses of the baseline cohort identified genes that are the target of recurrent gain-of-function and loss-of-function events. Consensus clustering identified 8 and 12 unique copy number and expression subtypes of myeloma, respectively, identifying high-risk genetic subtypes and elucidating many of the molecular underpinnings of these unique biological groups. Analysis of serial samples showed that 25.5% of patients transition to a high-risk expression subtype at progression. We observed robust expression of immunotherapy targets in this subtype, suggesting a potential therapeutic option. Longitudinal genomic and transcriptomic profiling of 1,143 patients with multiple myeloma by the Relating Clinical Outcomes in Multiple Myeloma to Personal Assessment of Genetic Profile study yields an improved copy number and gene expression subtype scheme, most notably a high-risk proliferative subtype associated with complete loss of RB1 or MAX.
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Multiple myeloma and MGUS/SMM have two key groups of initiating events: immunoglobulin (IGH) translocations and hyperdiploidy (HY).
“Historically, MM and MGUS/SMM have two key groups of initiating events: immunoglobulin (IGH) translocations and hyperdiploid (HY).9,54-59”
From Evolution of Multiple Myeloma from a Genomic Perspective (2026) · cites this paper as [57]
The Main section (page unavailable) describes two broad karyotypic groups in multiple myeloma: hyperdiploid tumors and non-hyperdiploid tumors that typically have an immunoglobulin translocation. The Results > Cohort description section (page unavailable) reports that most identified immunoglobulin translocations involved IGH. The copy does not establish these as initiating events or extend the grouping to MGUS/SMM. (LLM, conf=0.86)
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Badonyi, M., & Marsh, J. A. (2025) · Nature Communications · doi:10.1038/s41467-025-63234-3 · Cited by 19 · see citing works
“…skewed by study bias, in that multi-phenotype genes areoverrepresented indiseasegenes that have historically attracted more attention (e.g., TP53 , KRAS , and BRCA2 ), mLOF score analysisindicatesthat 43% of dominant and 49%of mixed-inheritance multi-phenotype genes exhibit phenotypes driven by…”
Evolution of Multiple Myeloma from a Genomic Perspective
Maura, F., Samur, M., & Munshi, N. (2026) · Blood · doi:10.1182/blood.2024026313 · Cited by 8 · see citing works
- Authors
- Skerget, S., Penaherrera, D., Chari, A., Jagannath, S., Siegel, D. S., Vij, R., Orloff, G., Jakubowiak, A., Niesvizky, R., Liles, D., Berdeja, J., Levy, M., Wolf, J., Usmani, S. Z., The MMRF CoMMpass Network, Rifkin, R., Meehan, K., Benson, D., Zonder, J., Ascensao, J., Gasparetto, C., Hernández, M., Trudel, S., Dakhil, S., Bahlis, N., Paganini, J. V., Rios, P., Sampol, A., Mannem, S., Silbermann, R., Lunning, M., Chu, M., Milner, C., Harroff, A., Graham, M., Shao, S., Dodlapati, J., de Larrea, C. F., Klein, L., Kuzma, C., Fonseca, R., Azaceta, G., Granell, M., Martinez-Chamorro, C., Balaraman, R., Silva, C., Chinea, A., Costello, C., Kambhampati, S., Lewis, D., Grossbard, M., Yost, K., Robles, R., Sebag, M., Harris, W., Ngaiza, J., Bar, M., Shieh, M., Min, F., Onitilo, A., Volterra, F., Wachsman, W., Yalamachili, M., Abella, E., Anderson, L., Bargay, J., Hassoun, H., Hsu, G., Kaya, H., Menter, A., Patel, D., Richards, D., Solomon, W., Anderson, R., Chandra, S., Conde, M., Girnius, S., Matkiwsky, M., Krsnik, I., Kumar, S., Oriol, A., Rodríguez, P., Roy, V., Srinivas, S., Steis, R., Christofferson, A. W., Nasser, S., Aldrich, J. L., Legendre, C., Benard, B., Miller, C., Turner, B., Kurdoglu, A., Washington, M., Yellapantula, V., Adkins, J. R., Cuyugan, L., Boateng, M., Helland, A., Kyman, S., McDonald, J., Reiman, R., Stephenson, K., Tassone, E., Blanski, A., Livermore, B., Kirchhoff, M., Rohrer, D. C., D’Agostino, M., Gambella, M., Collison, K., Stumph, J., Kidd, P., Donnelly, A., Zaugg, B., Toone, M., McBride, K., DeRome, M., Rogers, J., Craig, D., Liang, W. S., Gutierrez, N. C., Jewell, S. D., Carpten, J., Anderson, K. C., Cho, H. J., Auclair, D., Lonial, S., & Keats, J. J.
- Affiliations
- Translational Genomics Research Institute (US)
- Tisch Cancer Institute (US)
- Hackensack University Medical Center (US)
- Washington University in St. Louis (US)
- Virginia Cancer Specialists (US)
- University of Chicago Medical Center (US)
- East Carolina University (US)
- Baylor Scott & White Research Institute (US)
- University of California San Francisco Medical Center (US)
- Levine Cancer Institute (US)
- Rocky Mountain Cancer Centers (US)
- Dartmouth–Hitchcock Medical Center (US)
- The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (US)
- The Barbara Ann Karmanos Cancer Institute (US)
- Hospital Universitario de Canarias (ES)
- Princess Margaret Cancer Centre (CA)
- Cancer Center of Kansas (US)
- Hospital Universitario Infanta Sofía (ES)
- Hospital Universitario Nuestra Señora de Candelaria (ES)
- Oregon Health & Science University (US)
- Cross Cancer Institute (CA)
- University of Mississippi Medical Center (US)
- Waverly Hematology Oncology (US)
- Central Texas Veterans Health Care System (US)
- Hospital Clínic de Barcelona (ES)
- Cancer Care Specialists of Illinois (US)
- Mayo Clinic Hospital (US)
- Hospital de Sant Pau (ES)
- Yuma Oncology Center (US)
- Hospital Universitario Ramón y Cajal (ES)
- Kansas City VA Medical Center (US)
- Randolph Health (US)
- New York University (US)
- McGill University Health Centre (CA)
- Peninsula Regional Medical Center (US)
- Stamford Hospital (US)
- Holy Cross Hospital (US)
- Marshfield Clinic Research Foundation (US)
- VA San Diego Healthcare System (US)
- Hospital Del Mar (ES)
- Hospital Son Llatzer (ES)
- Memorial Sloan Kettering Cancer Center (US)
- San Francisco VA Medical Center (US)
- Kaiser Permanente (US)
- Texas Oncology (US)
- Maimonides Medical Center (US)
- Saint Barnabas Medical Center (US)
- University of Cincinnati (US)
- Hospital Universitario Puerta de Hierro Majadahonda (ES)
- Mayo Clinic (US)
- Clinica Universidad de Navarra (ES)
- East Orange VA Medical Center (US)
- Van Andel Institute (US)
- University of Turin (IT)
- Spectrum Health (US)
- Precision for Medicine (United States) (US)
- Multiple Myeloma Research Foundation (US)
- Harvard University (US)
- Emory University (US)
- Corresponding author
- Lonial, Sagar
- Keats, Jonathan J.
- ORCID
- Skerget, Sheri
- Chari, Ajai
- Jagannath, Sundar
- Siegel, David S.
- Vij, Ravi
- Jakubowiak, Andrzej
- Liles, Darla
- Berdeja, Jesus
- Levy, Moshe
- Wolf, Jeffrey
- Usmani, Saad Z.
- Rifkin, Robert
- Benson, Don
- Zonder, Jeffrey
- Gasparetto, Cristina
- Hernández, Miguel
- Trudel, Suzanne
- Dakhil, Shaker
- Bahlis, Nizar
- Rios, Pablo
- Silbermann, Rebecca
- Lunning, Matthew
- Chu, Michael
- Shao, Spencer
- Kuzma, Charles
- Azaceta, Gemma
- Granell, Miquel
- Chinea, Anabelle
- Costello, Caitlin
- Kambhampati, Suman
- Grossbard, Michael
- Yost, Kathleen
- Onitilo, Adedayo
- Wachsman, William
- Anderson, Larry
- Bargay, Joan
- Hassoun, Hani
- Kaya, Hakan
- Menter, Alex
- Conde, Miguel
- Krsnik, Isabel
- Kumar, Shaji
- Oriol, Albert
- Roy, Vivek
- Nasser, Sara
- Aldrich, Jessica L.
- Benard, Brooks
- Washington, Megan
- Yellapantula, Venkata
- Helland, Adrienne
- Kyman, Shari
- Tassone, Erica
- Rohrer, Daniel C.
- D’Agostino, Mattia
- Stumph, Jennifer
- Toone, Maureen
- Craig, David
- Liang, Winnie S.
- Gutierrez, Norma C.
- Jewell, Scott D.
- Carpten, John
- Anderson, Kenneth C.
- Cho, Hearn Jay
- Auclair, Daniel
- Lonial, Sagar
- Keats, Jonathan J.
- Venue
- Nature Genetics
- Published
- 2024-08-19
- Volume
- 56
- Issue
- 9
- Pages
- 1878-1889
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC11387199
- OpenAlex
- W4401702221
- Cited by
- 95
- References
- 3
- Citations by year
- 2026: 44 · 2025: 42 · 2024: 9
- FWCI
- 29.78
- Type
- journal article
- Language
- en
- Update notices
- correction (2025-06-09)
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Nature Genetics (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion, cc-by-nc-nd)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion, other-oa)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion, cc-by-nc-nd)
- Funders
- Multiple Myeloma Research Foundation (CoMMpass Study)
- Topics
- Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
- Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- multiple myeloma, molecular subtypes, copy number alterations, gene expression subtypes, tumor progression, RB1 loss, immunotherapy targets, precision medicine, plasma cell malignancy
- MeSH terms
- Whole Genome Sequencing, Exome Sequencing, Female, Humans, Longitudinal Studies, Male, Middle Aged, Multiple Myeloma, Gene Expression Regulation, Neoplastic, Disease Progression, Gene Expression Profiling, DNA Copy Number Variations
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